DESCRIPTION: (Applicant's Abstract) Five years of renewal funding are sought to study the etiology of substance abuse (SA) from a developmental behavioral genetic perspective. We hypothesize that an inherited predisposition to SA may be expressed in early adolescence as 1) personality characteristics, 2) psychophysiological markers, and 3) psychiatric disorder. Our findings to date indicate that these factors are a) strongly heritable, b) differentiate individuals with and without SA, c) differentiate individuals with and without an SA parent, d) prospectively predict the early initiation of drug and alcohol use in middle adolescence, and e) predict early onset drug and alcohol disorders in late adolescence. We have also found support for our hypotheses 1) that these phenotypic markers of liability influence SA risk in part by increasing the likelihood that an individual is both exposed to and affected by experiential risk factors during adolescence and 2) that gender may moderate the association between liability markers, environmental risk factors, and a psychoactive substance use disorder outcome. Six-hundred and sixty-six families consisting of a twin pair and their mother and father have completed a daylong, comprehensive assessment of their 1) mental health and substance use history, 2) personality (assessing the broad dimensions of positive emotionality, negative emotionality, and behavioral constraint), 3) psychophysiological markers (including brain potentials [P3 and EEG], autonomic nervous system measures, eye-blink startle, and eye tracking), and 3) environmental factors (including family climate, peer group, and cognitive risk factors). At study intake, the twins were either age 11 (an age prior to experimentation with drugs and alcohol) or age 17 (an age that precedes the adoption of adult substance use patterns). At the time of renewal, these families will have completed their first in-person follow-up (FU1) assessment at ages 14 and 20, three years after their initial intake assessment, and 40% will have completed FU2 at ages 17 and 23. Approximately half the children are at high risk by virtue of their having a parent with illicit drug abuse/dependence or alcohol dependence. During the next five years we propose to 1) complete FU2, 2) initiate FU3 (at ages 20 and 26), and 3) analyze the intake and FU data, comparing it to our parallel study of 717 female twin families (which is being augmented by the addition of another 200 twin families). The primary analyses to be undertaken during this funding period involve: 1) assessing the effects of parental SA, 2) univariate biometric analyses of the twin data, 3) multi variate biometric analyses aimed at exploring genotype-environment correlation, and 4) analysis of genotype-environment interaction effects.